The goal of this proposal is to decipher the genetic basis of inflammatory bowel disease (IBD) by integrating genome-wide association studies (GWAS) with the chromatin modification information in human immune system. Accumulating evidence suggests that IBD results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. Among complex diseases, GWAS methods have been successful in IBD, identifying hundreds of non-overlapping genetic risk loci. However, the majority of these disease-associated DNA variants fall into the gene-desert part of the genome, complicating their functional evaluation. There is now overwhelming evidence that the noncoding disease-associated DNA variants disrupt the action of key regulatory elements in relevant cell types. Since genomic coordinates of active regulatory elements can be charted using unique chromatin features, genome-wide profiling of chromatin modifications in relevant cell types can be used to pinpoint to DNA variants disrupting active regulatory elements. Two recent studies discovered a novel kind of enhancers that occurs within exceptionally large genomic domains. These regions were initially dubbed as 'super-enhancers'. Super-enhancer domains occur at key identity genes in a variety of cell types. Strikingly, these enhancer domains are more sensitive to perturbation such as loss of transcription factors than typical shorter enhancers. Because of the fragility of super-enhancers to perturbation, I postulate that super-enhancer domains of relevant immune cells harbor IBD-associated DNA variants. To test this hypothesis, in Aim 1 of this proposal, I will characterize super-enhancer structures of the human immune system. I will first develop an unsupervised machine learning technique to chart super-enhancer structures from histone acetylation (H3K27Ac) data in diverse immune cells. Using this technique, I will next delineate cell type- specific enhancer domains in the immune cells and investigate the relationship among cells types with respect to their super-enhancer structures. In Aim 2 of this proposal, I will investigate the enrichment of IBD-associated DNA variants within the super-enhancers of the most relevant immune cells. I then link these variants to genes and pathways that they regulate and are affected in disease utilizing gene expression and long-range chromatin interaction datasets. Completion of these aims, along with training opportunities associated with this proposal will establish the necessary foundation for my career as an independent investigator.